This invention relates to a process for preparing a 4-hydroxypyrimidine which is useful as a starting meterial for pharmaceuticals or agricultural chemicals.
The 4-hydroxypyrimidine is referred to as a 4-pyrimidone or a 4-pyrimidinol and preparation methods thereof have been described in detail, for example, in general remarks, D. J. Brown, "The chemistry of heterocyclic compounds, The Pyrimidines", 1962; "The chemistry of heterocyclic compounds, The Pyrimidines Supplement I", 1970; and "The chemistry of heterocyclic compounds, The Pyrimidines Supplement II", 1985 (all of them have been published by John Wiley & Son's Inc., New York).
In addition to the above described general remarks, a number of other preparation methods have been known as prior arts.
Typical preparation methods of a 4-hydroxypyrimidine which have conventionally been used in general and problems involved therein will be given below.
(i) A 4-hydroxypyrimidine is prepared according to a reaction between a .beta.-ketoester and an amidine (reaction scheme 1, G. W. Miller and F. L. Rose, J. Chem. Soc., 5642-5659 (1963). ##STR3## The reaction described above possibly gives a low yield in some cases depending on the kinds of the amidine employed (for example, formamidine). From industrial point of view, it is difficult to prepare the 4-hydroxypyrimidine at low cost since the amidin is expensive.
(ii) It is also possible to prepare a 4-hydroxypyrimidine by reacting a .beta.-ketoester and thiourea with each other, followed by desulfurization of the resulting product by use of Raney nickel (reaction scheme 2, Organic Synthesis, 35, 80, 1955). This method gives a high yield in general, however, from an industrial point of view, it has a serious drawback to employ Raney nickel which is expensive and difficult to handle. Moreover, according to this method, it is impossible to introduce a substituent to the 2-position. ##STR4##
(iii) There can also be mentioned a patent that a 3-amino-2-unsubstituted carboxylic acid amide and an acid halide or a carboxylate are reacted with each other to prepare a 4-hydroxypyrimidine (reaction scheme 3; Japanese Patent Publication Nos. 26020/1973 and 39942/1973). ##STR5##
Although this reaction proceeds easily, the 3-amino-2-unsaturated carboxylic acid amide except for 3-aminocrotonic acid amide is extremely difficult to be prepared as a starting material and therefore this reaction has been utilized with difficulty in practice.
(iv) There can also be mentioned a process in which a pyrimidine having previously a substituent on the 4-position is subjected to reaction to prepare a 4-hydroxypyrimidine (reaction scheme 4, H. Schroeder, J. Org. Chem., 27, 2580, 1962). ##STR6## However, this process requires preparation of a pyrimidine having a substituent on the 4-position.
(v) A process has also been reported that a 4-hydroxypyrimidine is prepared from a .beta.-ketoester, an ortho ester and ammonia (reaction schemes 5, V. D. Adams, Synthesis, 1974, [age 286). ##STR7##
This process involves not only a problem of a high cost of the ortho ester but also a problem of an extremely low yield when an ortho formate having no substitutent at the 2-position is used.
(vi) There has also been reported a process in which a 4-hydroxypyrimidine is prepared from a .beta.-ketoester, formamide and ammonia (reaction scheme 6, H. Brederck Ber., 90 942, 1957). ##STR8##
However, according to this process, 6-phenylpyrimidine only has been prepared at an extremely low yield.
As reactions similar to the present invention, there have been known a reaction in which a 4-hydroxyquinazoline is prepared from a 2-amino aromatic carboxylic acid such as anthoranilic acid or an ester thereof and formamide (U.S. Pat. No. 3,047,462) and a reaction in which a bicyclic 4-hydroxypyrimidine is prepared from a 2-aminocarboxylate having a hetero ring such as 3-aminopyrazole-4-carboxylate or 2-amonothiophene-3-carboxylate only through heating it with formamide (Advance in Heterocyclic Chemistry, 38 324, 1985). However, the compounds which have been actually used in the above reactions are those corresponding to a compound of Formula I described below in which R.sub.1 and R.sub.2 are connected to each other, and which are remarkably suitable for a cyclization reaction. When a compound in which R.sub.1 and R.sub.2 are not connected to each other is used, a desired product cannot be obtained even if the same reaction procedure as the above is carried out. U.S. Pat. No. 3,950,525 discloses that 6-phenyl-4-hydroxypyrimidine can be obtained from ethyl 2-aminocinnamate. However, this patent refers to a cinnamate derivative only but is silent about other derivatives. Further, the above reaction gives a low yield and takes a longer period for completion of the reaction, although a specific base such as potassium t-butoxide and a specific solvent such as dimethylsulfoxide are employed. Accordingly, it is difficult to apply this process for preparing other 4-hydroxypyrimidines in an industrial scale.
As described above, the conventional processes involve various problems therein in order to prepare a 4-hydroxypyrimidine industrially at a low cost.
In view from the circumstances described above, the present inventors have studied extensively a process for preparing a 4-hydroxypyrimidine which can be employed industrially, and completed the present invention.
The present invention provides a general method for preparing a 4-hydroxypyrimidine from a nono-cyclic 3-amino--2-unsaturated caboxylate and a carboxylic acid amide, which can be easily employed in an industrial scale and resolves the problems involved in the conventional processes.